Therapeutic Implications of the IL-21: IL-4 Receptor System in Children with Common Variable Immunodeficiency Syndrome

Abstract

Objectives: Interleukin-21 (IL-21) has been shown to restore immunoglobulin production together with Interleukin-4 (IL-4) in common variable immunodeficiency syndrome (CVID). Here, we elucidate the functional and structural properties of the corresponding IL-21R : IL-4R system.

Patients and Methods: An in vitro cell culture system was established to study the molecular effects of IL-21 and IL-4 on B cell differentiation, class-switch recombination (CSR) and immunoglobulin (Ig) production in 32 paediatric patients with CVID. MHC haplotypes and the IL21 and IL21R gene were analysed by genotyping. Ternary complexes of the IL-21 respectively IL-4 receptor were set-up by homology modeling and ligand-interaction was examined by molecular dynamics (MD) simulation.

Results: Stimulation with IL-21, IL-4 and CD40L uniformly induced IgG and IgA production in B cells from all tested patients by initiation of both CSR and AID-independent Ig production. No mutations were found in the coding regions of the IL21 or IL21R genes and no distinct HLA allele or extended haplotype could be correlated with the amount of Ig production or the gene expression pattern induced by IL-21. MD simulations of the modelled receptor complexes showed that IL-4 and IL-21 are both able to bind to IL-4R and IL-21R complexes in an interchangeable manner.

Conclusions: The function of the IL-21R : IL-4R system seems not to be related to the aetiology of CVID in paediatric patients and might be suitable for a regenerative therapy.

Zusammenfassung

Hintergrund: Experimentell kann die Immunglobulinproduktion bei Patienten mit variablem Immundefektsyndrom (CVID) durch Interleukin-21 (IL-21) und Interleukin-4 (IL-4) wiederhergestellt werden. Hier wurden Struktur und Funktion des zugehörigen IL-21/IL-4-Rezeptorsystems bei Kindern mit CVID untersucht.

Patienten und Methoden: Die Auswirkungen der Stimulation mit IL-21 und IL-4 wurden bei 32 Kindern mit CVID analysiert. Zusätzlich wurde der MHC-Haplotyp bestimmt und das IL21- und IL21R-Gen sequenziert. Wir erstellten Strukturmodelle des IL-21- und IL-4-Rezeptors, um die Rezeptor-Liganden-Interaktion durch Moleküldynamik (MD)-Simulationen zu untersuchen.

Ergebnisse: Unter Zellkulturbedingungen induzierte die Stimulation mit IL-21, IL-4 und CD40L bei allen Patienten eine vergleichbare IgG- und IgA-Produktion. In den kodierenden Bereichen des IL21- und IL21R-Gens fanden wir keine krankheitsverursachenden Mutationen. Korrelationen zwischen bestimmten HLA-Allelen und der Immunglobulinproduktion waren nicht nachweisbar. Die Auswertungen legen nahe, dass IL-21 und IL-4 duale Bindungseigenschaften am IL-21- und am IL-4-Rezeptor besitzen.

Schlussfolgerungen: Die Funktionen des IL-21/IL-4-Rezeptorsystems scheinen nicht mit dem Auftreten des variablen Immundefektsyndroms bei Kindern assoziiert zu sein und eignen sich für regenerative Therapien.

Key words

CVID - Interleukin-21 - class switch recombination - immunoglobulin production - B-cell differentiation

Schlüsselwörter

Variabler Immundefekt - Interleukin-21 - Immunglobulin-Klassenwechsel - B-Zell Differenzierung

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